Deubiquitination and Stabilization of PD-L1 by CSN5

Cancer Cell. 2016 Dec 12;30(6):925-939. doi: 10.1016/j.ccell.2016.10.010. Epub 2016 Nov 17.


Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.

Keywords: CSN5; PD-L1; TNF-α; anti-CTLA4; curcumin; deubiquitination.

MeSH terms

  • Animals
  • B7-H1 Antigen / chemistry
  • B7-H1 Antigen / metabolism*
  • COP9 Signalosome Complex
  • Cell Line, Tumor
  • Curcumin / pharmacology
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • NF-kappa B / metabolism*
  • Neoplasm Transplantation
  • Neoplasms / metabolism*
  • Peptide Hydrolases / metabolism*
  • Protein Stability
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ubiquitination


  • B7-H1 Antigen
  • CD274 protein, human
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Peptide Hydrolases
  • COPS5 protein, human
  • COP9 Signalosome Complex
  • Curcumin